Effects of apigenin on gastric cancer cells

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Highlights​

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  Apigenin has anti-proliferative ability towards gastric cancer cells through induction of apoptosis.
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  Apigenin decreases the inflammatory response to Helicobacter pylori and the production of reactive oxygen specimens.
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  Apigenin might be a therapeutic option to counteract progression of HP-induced inflammation into gastric cancer.
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  Apigenin has the potential to be used has a therapeutic option to restrain gastric cancer cell growth.

 

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Abstract​

Gastric Cancer (GC) is one of the most prevalent cancers worldwide. As the currently available therapeutic options are invasive, new and more benign options are being explored. One of which is Apigenin (Api), a natural flavonoid found in fruits and vegetables, such as celery, parsley, garlic, bell pepper and chamomile tea. Api has known anti-inflammatory, -oxidant, and -proliferative proprieties in several diseases and its potential as an anticancer compound has been explored. Here we systematize the available data regarding the effects of Api on GC cells, in terms of cell proliferation, apoptosis, Helicobacter pylori (H. pylori) infection, and molecular targets. From the literature it is possible to conclude that Api inhibits cell growth in a dose- and time-dependent manner, which is accompanied by the reduction of clone formation and induction of apoptosis. This occurs through the Akt/Bad/Bcl2/Bax axis that activates the mitochondrial pathway of apoptosis, resulting in restriction of cell proliferation. Additionally, it seems that the anti-proliferative potential of Api on GC cells is particularly relevant in a more aggressive GC phenotype but can also affect normal gastric cells. This indicate that this flavonoid must be used in low-to-moderate doses to avoid side-effects induced by disturbance of the normal epithelium. In H. Pylori-infected cells, the literature demonstrates that Api reduces inflammation by diminishing the levels of H. pylori colonization, by preventing NF-kB activation and by diminishing the production of reactive oxygen specimens (ROS). Accordingly, in GC Api seems to regulate different hallmarks of cancer, such as cell proliferation, apoptosis, cell migration, inflammation and oxidative stress, demonstrating its potential has an anti-GC compound.

 

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1. Introduction​

Gastric Cancer (GC) is one of the most prevalent tumours worldwide, being the second mostly deadly cancer [23], [40]. GC is asymptomatic or has nonspecific symptoms in early stages of the disease and when the symptoms are apparent it is usually already in an advanced stage which translates in a worse prognosis [8]. Treatment of GC is based on surgery for total or partial removal of the affected area, when it is still restricted to the gastric mucosa – early stages – and chemotherapy for more advanced stages, both of which are quite invasive and aggressive procedures for the patient [31]. Accordingly, over the last few years, efforts have been made to develop more suitable therapeutic strategies and new doors have been opened with the study of natural compounds with potential anticancer effects. One such compound is apigenin (Api), known chemically as 4',5,7-trihydroxyflavone, that is one of the most common flavonoids, and can be found in fruits and vegetables, with particular abundance in celery, parsley, garlic, bell pepper and chamomile tea [16]. Api has a wide range of pharmacological properties and has been used in traditional medicine for centuries, mainly due to its anti-inflammatory, -oxidant, -toxic, -bacterial, -viral, -parasitic, -fungal, -diabetic, -allergic and hemostatic properties [36], [52]. Chamomile, which is one of the highest sources of Api, has been reported to be effective in relieving gastritis symptoms and is used as an inhalant vapor that reduces inflammation, and in skin care products [48]. Several pharmacokinetic studies established that Api reverses the adverse effects of cyclosporine-induced kidney damage, exerted immunomodulatory effects against rheumatoid arthritis and other autoimmune diseases [1]. Api has also been shown to have protective effects against Alzheimer and Parkinson diseases, as well as ischemic reperfusion injury, cardiovascular disease, amnesia. Additionally, this flavone has beneficial effects in cases of depression and insomnia [11], [14], [19], [2], [21], [27], [45], [47], [51], [55], [57]. The first study on the anti-mutagenic effects of Api was carried out by Birt et al. in 1986 and since then the anticancer and antiproliferative effects, as well as the pathways affected by the Api, have gained interest from the scientific community [4]. More recently, it has been proven that Api is an effective compound in tumour suppression of several types of cancers, namely colorectal, breast, prostate, oral and liver cancer, as well as some types of leukaemia [20], [35], [38], [46], [53], [9]. The evolution of any type of neoplasia is a complex process that involves a series of genetic and epigenetic alterations that lead to the initiation, promotion and cancer progression [12]. These alterations consist of over- or under-expression of proteins that regulate different biological processes, usually in processes such as proliferation, differentiation and survival [12]. With the various studies carried out to date, it is known that Api inhibits cell growth and proliferation, promotes apoptosis, induces cell cycle arrest and autophagy and is able to disrupt the mitochondrial membrane potential in vivo and in vitro [18], [25], [50], [54], [8]. Nevertheless, there is no systematization of the mode of action of Api in GC: Accordingly, here we review the studies addressing the role of Api on GC in terms of cell proliferation, apoptosis, Helicobacter pylori (H. pylori) infection and molecular targets.